Molecular Evidence for Altered Angiogenesis in Neuroinflammation-Associated Schizophrenia and Bipolar Disorder Implicate an Abnormal Midbrain Blood-Brain Barrier

Abstract

Background and Hypothesis Angiogenesis triggered by inflammation increases BBB permeability and facilitates macrophage transmigration. In the midbrain, we have discovered molecular alterations related to the blood-brain barrier (BBB), including endothelial cell changes associated with macrophage diapedesis, in neuroinflammatory schizophrenia and bipolar disorder, but changes in angiogenesis are yet to be reported. Hypothesis: We expected to discover molecular evidence of altered angiogenesis in the midbrain in individuals with schizophrenia and bipolar disorder compared to controls, with these changes more evident in “high” inflammation schizophrenia as compared to “low” inflammation. Study Design In a case-control post-mortem cohort including schizophrenia (n = 35), bipolar disorder (n = 35), and controls (n = 33), we measured mRNA (RT-PCR) and protein (multiplex immunoassays) and performed immunohistochemistry to determine levels and anatomical distribution of angiogenesis-related molecules in the ventral midbrain. Study Results We found large changes in angiogenesis factors in bipolar disorder high inflammatory subgroup (increased angiopoietin-2 and SERPINE1 mRNAs, but decreased angiopoietin-1, angiopoietin-2, and TEK receptor proteins). In schizophrenia high inflammatory subgroup, we found a robust increase in SERPINE1 mRNA and protein levels. However, we found no significant changes in angiopoietins in schizophrenia. We found that VEGFA mRNA level was increased in high inflammation schizophrenia, but only reached statistical significance compared to one low inflammatory subgroup. Conclusions Thus, angiogenesis signaling pathways appeared to be involved in the BBB alterations when inflammation is also present in the midbrain of schizophrenia and bipolar disorder, with increased levels of SERPINE1 in schizophrenia high inflammatory subgroup and with a putative suppression of angiopoietin signaling in bipolar disorder high inflammatory subgroup.